From the Guidelines
APOE4, or Apolipoprotein E4, is a genetic variant that significantly increases the risk of developing Alzheimer's disease, particularly late-onset Alzheimer's disease, with carriers having a 2-3 fold increased risk for heterozygotes and up to 10-fold increased risk for homozygotes 1. The APOE gene has three isoforms: ε2, ε3, and ε4, with the ε4 variant being associated with an increased risk for Alzheimer's disease.
- Approximately 50-70% of people with Alzheimer's disease carry at least one ε4 allele, with this percentage increasing in those with a positive family history of the disease.
- The presence of an ε4 allele increases the risk of Alzheimer's disease in a dose-dependent fashion, with individuals having two copies of the ε4 allele being at the highest risk.
- The ε4 allele is thought to influence the age at which Alzheimer's disease occurs, rather than the overall lifetime risk for the disease. Key points about APOE4 include:
- Its association with an increased risk of other diseases, such as cardiovascular disease and macular degeneration.
- The potential protective role of the ε2 allele against developing Alzheimer's disease.
- The importance of considering APOE4 in the context of genetic counseling and testing for Alzheimer's disease, as first-degree relatives of an affected individual are estimated to have a 15-39% lifetime risk of developing the disease 1. In clinical practice, it is essential to consider the APOE4 variant when assessing an individual's risk for Alzheimer's disease, particularly in those with a family history of the disease, to provide personalized prevention strategies and potential treatments 1.
From the Research
Definition and Role of APOE4
- APOE4 is the first identified genetic risk factor and remains the strongest predictor for late-onset Alzheimer's disease (AD) 2.
- It is a variant of the apolipoprotein E (APOE) gene, which plays a crucial role in lipid metabolism and transport in the brain 3, 4.
- APOE4 contributes to the formation of tau tangles, deposition of Aβ, neuroinflammation, and other processes associated with AD pathology 2, 5, 4.
Effects of APOE4 on Brain Cell Types
- APOE4 affects different brain cell types, including neurons, astrocytes, and microglia, leading to various molecular and cellular alterations associated with AD phenotypes 5.
- In neurons, APOE4 increases synapse number and elevates Aβ42 secretion, while in astrocytes, it impairs Aβ uptake and leads to cholesterol accumulation 5.
- In microglia-like cells, APOE4 alters morphologies and reduces Aβ phagocytosis, contributing to neuroinflammation and AD pathology 5.
Therapeutic Strategies Targeting APOE4
- Reducing APOE4 expression or activity has been proposed as a promising therapeutic strategy for the treatment of AD patients carrying the APOE ε4 allele 2, 4.
- Administration of apoE antisense oligonucleotides or apoE siRNAs has been shown to alleviate AD pathologies in mouse models 2.
- Targeting APOE4's detrimental effects may also involve modulating its metabolic receptor LDLR or other related pathways 2, 4.